Disease relevance of Hmga2

• In vivo modulation of Hmgic reduces obesity [1].
• Similar truncations of murine Hmga2 in transgenic mice result in somatic overgrowth and, in particular, increased abundance of fat and lipomas, features strikingly similar to those observed in the child [2].
• Here, we report that HMGI-C/T TG mice develop natural killer (NK)-T/NK cell lymphomas starting from 12 months of age [3].
• We have previously demonstrated that transgenic (TG) mice carrying a truncated HMGI-C construct (HMGI-C/T) exhibit a giant phenotype together with a predominantly abdominal/pelvic lipomatosis [3].
• Elevated expression of the three high-mobility group I (HMGI) proteins (HMGI, HMGY, and HMGI-C) has previously been correlated with the presence of a highly malignant phenotype in epithelial and fibroblastic rat thyroid cells and in experimental thyroid, lung, mammary, and skin carcinomas [4].

High impact information on Hmga2

• Disruption of Hmgic caused a reduction in the obesity induced by leptin deficiency (Lepob/Lepob) in a gene-dose-dependent manner [1].
• To study its role in adipogenesis and obesity, we examined Hmgic expression in the adipose tissue of adult, obese mice [1].
• Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C [5].
• These proteins have been implicated in adipocyte homeostasis: a severe deficiency of fat tissue is found in mice with targeted disruption of the HMGI-C locus, and lipomagenesis in humans is frequently associated with somatic mutations of HMGI genes [6].
• The high-mobility group I (HMGI) nonhistone chromosomal proteins HMGI(Y) and HMGI-C have been implicated in defining chromatin structure and in regulating the transcription of several genes [6].

Biological context of Hmga2

• Transfection experiments indicate that non-B-DNA conformers of the ppyr/ppur tract of the Hmga2 promoter contribute to positive transcriptional activity [7].
• Various genes that mapped to the distal end of Chromosome (Chr) 10 were considered as possible candidates for the mouse pygmy (pg) locus [8].
• HMGI-C is a nuclear architectural factor which is expressed during embryogenesis but not in adult tissues while it becomes re-expressed following neoplastic transformation [9].
• Here, we report that chromosomal translocations previously associated with human tumors disrupt repression of High Mobility Group A2 (Hmga2) by let-7 miRNA [10].
• Since the human homolog is disrupted in a number of tumors, HMGI-C could play an important role in cell proliferation and differentiation during mammalian development [11].

Anatomical context of Hmga2

• Our studies implicate a role for HMGIC in fat-cell proliferation, indicating that it may be an adipose-specific target for the treatment of obesity [1].
• Inhibition of HMGI-C protein synthesis suppresses retrovirally induced neoplastic transformation of rat thyroid cells [4].
• The HMGIC 5' flanking sequences had constitutive promoter activity in all cell lines tested, suggesting that HMGIC is regulated by negative regulatory elements that were not present in the 5'-flanking regions analysed here [12].
• Mouse spinal cord (4.4 pg equivalents/micrograms RNA) had the lowest levels of NMDAR1 mRNA [13].
• In the mouse CNS the highest levels of NMDAR1 mRNA were found in the olfactory bulb (12.9 pg equivalents/micrograms RNA), followed closely by hippocampus, frontal cortex and cerebellum [13].

Associations of Hmga2 with chemical compounds

• In the kidney, a decrease was observed within 21 days, from 43 +/- 4 and 40 +/- 4 to 29 +/- 2 and 22 +/- 1.7 pg/micrograms in controls and DHT-treated groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)[14]
• Heart Ang II level in the F(6) transgenic mice increased nearly threefold (1984 +/- 184 versus 568 +/- 88 pg/g protein) ( P < 0.05) but was unchanged in plasma [15].
• Based on the specific activity of the methionine precursor, the absolute rate of synthesis was calculated to be about 50 pg protein/oocyte/hour [16].
• At age 50 days, the content (expressed as pg/testis) of androstenedione, testosterone, and DHT was reduced in ethanol-treated animals by 49%, 31%, and 38%, respectively, as compared to that of their respective controls [17].
• NS-398 treatment of injured mice decreased PGE(2) production compared to T (3.9 +/- 0.3 vs 3.1 +/- 0.4 pg/microg protein), and significantly decreased IL-6, NO, and TNF-alpha production [18].

Regulatory relationships of Hmga2

• NF-kappaB mediated transcriptional activation is enhanced by the architectural factor HMGI-C [19].
• To determine whether HMGI proteins are also required for in vivo thyroid carcinogenesis, mice carrying a disrupted HMGI-C gene (pygmy mice) were either treated with radioactive iodine or crossed with transgenic mice carrying the E7 papilloma virus oncogene under the transcriptional control of thyroglobulin gene promoter [20].

Other interactions of Hmga2

• The HMGI family consists of three members: HMGI, HMGY and HMGI-C [21].
• In this paper we show for the first time that HMGI-C is also able to function as architectural factor, enhancing the activity of a transcription factor, NF-kappaB, through the PRDII element of the beta-interferon enhancer [19].
• High mobility group I proteins (HMGI, HMGY and HMGI-C) are a family of low molecular mass non-histone nuclear proteins which constitute an important component of the active chromatin structure [19].
• Mutations in the genes for high mobility group protein I-C (HMGI-C) and insulin-like growth factor 1 (IGF1) are known to be responsible for dwarf phenotypes in the mouse [22].

Analytical, diagnostic and therapeutic context of Hmga2

• Using gel-retardation assay, we demonstrate that two members of the high mobility group I (HMGI) family of nuclear proteins (HMGI-C and HMGY) can bind to a subset of HD target sequences and inhibit HDs from binding to the same sequences [23].
• The technique of RNA in situ hybridization to mouse embryo sections from different developmental stages was used to perform a detailed analysis of the expression pattern of the gene for the architectural chromatin factor Hmgic [24].
• Northern blot analysis showed no difference in the expression of the HMGI-C gene between adw and wild-type chicken embryos [22].
• Utilization of a microdissection technique followed by quantitative solution hybridization of RNA extracts from mouse brain revealed mean levels of DOR mRNA ranging from 3.9 pg/micrograms RNA in the caudate-putamen to 0.4 pg/micrograms RNA in the cerebellum [25].
• The approach combines global PCR and 77 RNA polymerase amplification and allows the preparation of labeled, amplified RNA for array hybridization from single murine blastocysts containing approximately 1.5 pg mRNA in less than 12 h [26].

References